Heartburn is the most frequent symptom of gastrointestinal origin. Despite many published observations, how and why it occurs--and does not occur more frequently--are largely unknown. Until we know some of these hows and whys, treatment of this symptom must remain empirical--neither rational nor highly effective. We have previously presented convincing evidence for the importance of gastrin in the maintenance of lower esophageal sphincter (LES) competence. In fact, our data to date suggests that patients with severe clinical gastroesophageal reflux have a weak LES because they have decreased circulating gastrin activity. Simple gastrin deficiency cannot explain this apparent decrease in gastrin activity because others have shown that absolute levels of immuno-assayable gastrin are normal in these patients. The sharply-peaked pentagastrin-LES dose-response curve we have found seems to provide a handle allowing us to gather evidence favoring one of several alternate mechanisms, however, since pilot studies in normals have shown that the pentagastrin dose producing peak LES response is determined by circulating gastrin activity. These studies will be refined in normals and extended to subjects with clinical gastroesophageal reflux. We will also quantitate the change in gastrin activity induced by variations in antral (H ion). These studies will also be done in both normals and abnormals. A pilot study has recently shown that LES strength varies as the pH of the distal esophagus varies. These studies will also be continued and broadened to include patients with clinical LES incompetence. An intriguing form of LES incompetence - heartburn of pregnancy -has received relatively little attention. Since our studies have shown that hormones are important in non-pregnant individuals, we plan to see if this reversible LES incompetence might also have a hormonal origin.